9alpha-halo-11-keto-17-alkyltestosterones



2,793,218 9a-HALO-11-KETO-l7 -ALKYLTESTOSTERONES 5 Milton E. Herr,Kalamazoo, Mich., assignor to The Upjohn Company, Kalamazoo, Mich., acorporation of Michigan No Drawing. Original application August 8, 1955,Serial No. 527,118. Divided and this application May 10, 1956, SerialNo. 583,922

3 Claims. (Cl. 260397.45)

This invention relates to novel 17 -alkyl-17-hydroxy steroids and estersthereof.

It is an object of this invention to provide novel 91:- halo 11,8hydroxy 17 alkyltestosterones, 9a halo- 1] keto 17 alkyltestosteroncs,l7-esters thereof, and intermediates in the production thereof. Anotherobject is the provision of processes for the production thereof. Otherobjects will be apparent to those skilled in the art to which thisinvention pertains.

According to the present invention, the novel 9a-halollB hydroxy 17alkyltestosterones, 9a halo 11- keto 17 alkyltestosterones and 17 estersthereof may be prepared from 9(11) dehydro 17 alkyltestosterone via theknown 3 pyrrolidyl enamine of 4,9(11)-androstadiene 3,17 dione (II)[Heyl and Herr, I. Am. Chem. Soc., 77, 489 (1955)], 115 hydroxy 17methyltestosterone or esters thereof (I) or 110: hydroxy 17-methyltestosterone or esters thereof (U. S. Patent 2,660,- 586) (I) asshown by the following formulae:

CH: CH:

0-11 0 orn 9 1 H0 t 1 1 CH; CH;

O-R' O-R' CHa L-- CH;

IV III OH! CH;

OR' O-R' L- HO CH0 s on.

l l O= O:

- V .the 9a-fluoro and 9a-Ohi0l'0 compounds.

r 2,793,218 Patented May 21, 19.57

VIII VII wherein R is a lower-alkyl group containing less than threecarbon atoms, i. e., methyl or ethyl; R is hydrogen or the acyl radicalof a hydrocarbon carboxylic acid containing from one to twelve carbonatoms, inclusive; X

is a halogen having an atomic weight from 79 to 127, in-

clusive, i. e., bromine or iodine, X is a halogen having an atomicweight from 19 to 36, inclusive, i. e., fluorine or chlorine, and X" isa halogen having an atomic weight from 19 to 127, inclusive, i. e.,fluorine, chlorine, bromine 20 or iodine.

Following the series of reactions described hereinafter for theconversion of 11a. hydroxy 17 methyltestosterone (I) to 9a. hydroxy 17methyltestosterone testosterone and esters thereof (VII), butsubstituting 10- normethyl 11o: hydroxy 17 methyltestosterone (U. S.Patent 2,660,586) as the starting steroid, there are thus produced 911fluoro 10 normethyl 11B hydroxy 17 methyltestosterone and 17 estersthereof. These compounds are also potent oral anabolic agents possessingandrogenic activity.

Reacting 9(11)-dehydro-17-methyltestosterone with a molar excess ofdiethyl oxalate and a molar equivalent of sodium methoxide in tertiarybutyl alcohol is productive of the sodium enolate of the Z-ethoxyoxalylderivative thereof. After neutralization of the solution with aceticacid and then brominating with a molar equivalent of bromine at aboutminus ten degrees centigrade, 2- bromo 2 ethoxyoxalyl 9(11) dehydro l7methyltestosterone is produced. After removing the Z-ethoxyoxalyl groupwith sodium methoxide in methanol, the 2- bromo-9( l1)-dehydro-17-methyltestosterone is dehydrohalogenated with refluxingcollidine to 3-keto-17a-methyl- 1,4,9(11) androstatrien-Ufl-ol.Employing this compound as the starting steroid in the reactions for theconversion of 9(11)-dehydro-17-methyltestosterone to 90:-fluoro-llfl-hydroxy-17-methyltestosterone and 17-esters thereof, thereare thusproduced3-keto-9a-fluoro47amethyl-1,4-androstadiene-11,8,17JS-diol and 17-estersthereof, e. g., a hydrocarbon carboxylic acid ester containing from oneto twelve carbon atoms, inclusive, for example, of an acid named in theparagraph following Example 4. These compounds also possess androgenicactivity and marked oral anabolic activity.

The novel 9a-halo-11ehydroxy-l7-alkyltestosterone and 17-esters thereof(VII) and 9a-halo-11-keto-17-alkyltestosterone and 17-esters thereof(VIII) possess marked androgenic activity and oral anabolic activity.For example, 9a-fluoro-1lp-hydroxy-l7-methyltestoterone possesses anoral anabolic activity about eighteen to nineteen times and an oralandrogenic activity about ten times that of l7-methyltestosterone.Furthermore, it is considerably less toxic, and, surprisingly, it doesnot demonstrate the undersirable salt retention side-effect which onemight expect of a 9a-fluoro compound. 9ufluoro-1l-keto-l7-methyltestosterone possesses an oral androgenie activitywhich is more than twice that of l'l-methyltestosterone and its oralanabolic activity is more than five times that of 17-methyltestosterone.Similarly, the

corresponding 9u-chloro analogues possess high' oral anabolic andandrogenic activities as do the 17-esters of both 9a-brornoand9a-iodo-ll-keto-l7-methyltestosterone and their 17-esters also possessanabolic and androgenic activity.

The novel androgens and anabolic agents of this invention, especiallyVII and VIII, are useful as male gonadal replacement therapy inprepuberal and post puberal castrates, in pituitary dwarfism, Simmondsdisease, dysmenorrhea and for suppression of lactation. Their anabolicactivity is useful in increasing weight, muscle strength and forincreasing the sense of well-being and positive nitrogen balance inpituitary deficiencies. By adjustment of the dose, a favorable anabolicresponse can be achieved without noticeable androgenic response, if thisis desired.

The novel androgen and anabolic agents of the present invention arenormally administered orally, e. g., as tablets, capsules or in the formof flavored fluid prep arations, in which may additionally beincorporated, if desired, an estrogen, e. g., estrone, estradiol,estradiol-Zl- B-cyclopentylpropionate, for combined androgen-estrogentherapy.

The following examples are illustrative of the products and processes ofthe present invention, but are not to be construed as limiting.

Example I .9( 1 I )-dehydro-1 7-methyltestosterone (I V) To a stirredsolution of 100 grams of llB-hydroxy-4- androstene-3,17-dione in oneliter of dry pyridine was added, at room temperature and in a nitrogenatmosphere, sixty grams of N-bromoacetamide all at once. The resultingmixture was stirred for fifteen minutes and then cooled to ten degreescentigrade. Into the cooled solution was bubbled sulfur dioxide gasuntil the mixture gave a negative test with acidified starch-iodidepaper. The mixture was diluted with four liters of water and cooled toabout zero degrees centigrade for three hours. There was thusprecipitated 4,9(1l)-androstadicne-3,17-dione [Heyl and Herr, J. Am.Chem. Soc., 77, 488 (1955)], which after filtering, washing with waterand drying, weighed eighty grams and melted at 197 to 203 degreescentigrade.

To a hot solution of 56.8 grams of 4,9(1l)-androstadiene-3,l7-dione in800 milliliters of methanol was added 25 milliliters of pyrrolidine,whereupon product began to precipitate almost immediately. The solutionwas permitted to cool to room temperature and then was refrigerated atzero degrees centigrade for three hours. The crystalline precipitate wasfiltered, washed with methanol and then dried to give 59 grams of the3-enamine of 4,9(11)androstadiene-3,l7-dione (II) (3-pyrrolidyl-3,5,9,(ll)-androstatrien-l7-one) (Heyl and Herr, loc. cit.) melting withdecomposition above 165 degrees centigrade.

To a stirred solution of 700 milliliters of a four molar solution ofmethyl magnesium bromide in diethyl ether was added, dropwise and in anitrogen atmosphere, a solution of 59 grams of the B-enamine of4,9(1l)-androstadiene-3,l7-dione (II) in one liter of strictly anhydroustetrahydrofuran over a period of fifteen minutes. When addition wascomplete the mixture was warmed and the solvent distilled therefromuntil the distillation temperature reached sixty degrees centigrade.While protecting it from moisture and atmospheric oxygen, the mixturewas refluxed for eighteen hours. The solution was then cooled in anice-water bath and 430 milliliters of water was then cautiously addedthereto. With the mixtuer still under a nitrogen atmosphere, there wasthen added 260 milliliters of glacial acetic acid followed by one literof methanol and the mixture was then heated until all the precipitated3-enamine of 9(11)-dehydro-l7-methyltestosterone (III) had dissolved.

To the solution containing the 3-enamine of 9(1l)-dehydro-l7-methyltestosterone (III) was then added 700 milliliters often percent aqueous sodium hydroxide and the mixture was then heated atits refluxing temperature for thirty minutes to hydrolyze the enaminegroup, thereby regenerating the A-3-keto group. The mixture was thencooled to room temperature, acidified with acetic acid and thendistilled at reduced pressure until a residual volume of about 1.5liters was reached. After adding a mixture of milliliters ofconcentrated hydrochloric acid and 100 grams of ice, the residue wasextracted with 800, 500, 400 and 400 milliliter portions of methylenechloride. The combined extracts were washed successively with water,dilute sodium hydroxide and water and then dried. The solvent wasdistilled from the dried solution and the residue dissolved in amixtureof 100 milliliters of methylene chloride and 250 milliliters of benzeneand chromatographed over 700 grams of activated alumina. The column wasdeveloped with 500 milliliters of benzene, two liters of Skellysolve Bhexane hydrocarbons plus four percent acetone, two liters of SkellysolveB plus seven percent acetone, two liters of Skellysolve B plus elevenpercent acetone, four liters of Skellysolve B plus fourteen percentacetone and finally. two liters of Skellysolve B plus seventeen percentacetone. The eluate fractions containing from eleven to seventeenpercent acetone were combined and the solvent distilled therefrom togive crude product which, when crystallized from dilute acetone, gave26.8 grams of 9(ll)-dehydrol7-methyltestosterone (IV) melting at 167 to170 degrees centigrade.

Following the procedure of Example 1 exactly, but substituting ethylmagnesium bromide for the methyl magnesium bromide, there isthus-produced 9(l1)-dehydroxy-l7-ethyltestosterone.

Example 2 .-9( I I -dehydro-] 7-methyltestosterone (IV) One-half gram of1l-keto-17a-methyltestosterone (U. 5. Patent 2,678,933) was dissolved inthree milliliters of absolute methanol and mixed with one-halfmilliliter of pyrrolidine at a temperature of about fifty degreescentigrade. The mixture was allowed to cool to room temperature, and,after about one-half hour, the B-enaminc of1l-keto-lT-methyltestosterone [3-(N-pyrrolidyl)-17amethyl-l78-hydroxy-3,S-androstadien-ll-onel which had precipitated was removed byfiltration and dried under vacuum. The yield of high purity 3-enamineproduct was 0.452 gram melting at to degrees centigrade withdecomposition.

A solution of 1.79 grams of the 3-enamine of llketol7a.-methyltestosterone in a mixture of 25 milliliters ofthiophene-free benzene and 25 milliliters of anhydrous ether was addeddropwise with mechanical stirring to a mixture of one-half gram oflithium aluminum hydride and 85 milliliters of dry ether. The additionrequired about five minutes and stirring was continued for an additionalfifteen minutes. Then with stirring. ten milliliters of ethyl acetatewas cautiously added dropwise. followed by ten milliliters of water. Theresulting mixture was concentrated in vacuo to a thick slurry. Onehundred milliliters of methanol was then added and the mixture stirredfor ten minutes at a temperature of about fifty degrees centigrade. Theneighteen milliliters of five percent aqueous sodium hydroxide was addedand the stirring continued at the same temperature for another tenminutes. After addition of five milliliters of acetic acid, the mixturewas concentrated in vacuo. A mixture of fifty milliliters of water andeight milliliters of concentrated hydrochloric acid was added, and thesolid product was recovered by filtration, washed with water, and driedin air. The yield of 1lfi-hydroxy-l7w methyltestosterone (I) was 1.29grams; melting point 207 degrees centigrade. Recrystallization from amixture of methylene chloride and Skellysolve B hexane hydrocarbons gave0.977 gram of 1lfl-hydroxy-l7a-methyltestosterone; melting point 209 to211 degrees centigrade and having an [aJ of plus 128 degrees inchloroform.

Analysis-Calculated. for CznHssOa: C, 75.44; H, 9.49. Found: C, 75.14;H, 9.85.

To a stirred solution of one gram of 11B-hydroxy-17- methyltestosterone(I) in ten milliliters of dry pyridine was added, portionwise at 25degrees centigrade and in a nitrogen atmosphere, 0.5 gram ofN-bromoacetamide. Stirring was continued for fifteen minutes, themixture then cooled to ten degrees centigrade and sulfur dioxide gas wasbubbled into the cool solution until a negative test with acidifiedstarch-iodide paper was obtained. Ten milliliters of water was thenadded to the mixture followed by a mixture of fifteen milliliters ofconcentrated hydrochloric acid mixed with 25 grams of ice. Theprecipitated solid was separated, washed with water, dried and thencrystallized first from a mixture of methylene chloride and SkellysolveB (hexane hydrocarbons) and then from dilute acetone to give 9(l1)-dehydro-l7-methyltestosterone melting at 170 to 172 degreescentigrade.

Example 3 .9 (1 1 -dehydro-1 7-m ethylestosterone (I V) A warm solutionof one gram of 1lwhydroxy-17- methyltestosterone (I, U. S. Patent2,660,586) in two milliliters of dry pyridine was mixed with one gram ofpara-toluenesulfonyl chloride. The mixture was maintained at roomtemperature for eighteen hours and then poured into 25 milliliters ofwater. The mixture was stirred until the precipitated oil solidified.The solid was filtered, washed with water and dried to give 1.41 gramsof 11a (p toluenesulfonyloxy) 17a methyl 17,8 hydroxy-4-androsten-3-onewhich melted at 144 to 148 degrees centigrade with decomposition and,after crystallization from a mixture of methylene chloride and hexanehydrocarbons, melted at 141 to 144 degrees centigrade with decompositionand had an [a] of plus 41 degrees in chloroform and the analysis below.

Calculated for C2'TH3605SI C, 68.61; H, 7.68; S, 6.78. Found: C, 68.86;H, 7.86; S, 6.89.

A mixture of one gram of the thus-produced Ila-(ptoluenesulfonyloxy) 17amethyl 17B hydroxy 4 androsten-B-one, 0.2 gram of sodium formate, 0.57milliliter of water and fourteen milliliters of absolute ethanol washeated at its refluxing temperature for nineteen hours. The solution wascooled and then poured onto fifty grams of a mixture of ice and waterwith stirring. The resulting precipitate was filtered and dried to give0.59 gram of 9(11)-dehydro-17-methyltestosterone which melted at 156 to160 degrees centigrade and, after crystallization from a mixture ofmethylene chloride and hexane hydrocarbons, melted at 167 to 170 degreescentigrade and had an [oc] of plus 57 degrees in chloroform and theanalysis below:

Calculated for CatrHasOz: C, 79.96; H, 9.39. Found: C, 79.59; H, 9.08.

Example 4.9 (11 -dehydro-17-methyltestoster0ne, I 7- acetate (IV) Asolution of 9(1l)-dehydro-l7-methyltestosterone in dry pyridine wastreated with acetic anhydride, the molar ratio of steroid to aceticanhydride being about one to three, and the resulting mixture was heatedunder reflux for six hours. The mixture was then cooled, diluted withwater while stirring, and the solid precipitate obtained removed byfiltration. The solid was washed with two percent aqueous hydrochloricacid solution and with water, and then dried under vacuum.Recrystallization or chromatographic separation provides purified 9(1l)-dehydro-l7-methyltestosterone, l7-acetate. Similarly, 9(1 1)-dehydro-l7-methyltestosterone is converted to other9(1l)-dehydro-l7-methyltestosterone, l7-acylates by esterification ofthe l7-hydroxy group, e. g., by reaction with the appropriate acidanhydride, acid chloride or bromide, ester by ester exchange, acid inthe presence of esterification catalyst, etc. Examples of9(1l)-dehydrol7 methyltestosterones, l7 acylates (IV, R=CH3, R=Acyl)prepared include those wherein the acyl group is the acyl radical of,for example, a lower-aliphatic acid, e. g., formic, propionic, butyric,isobutyric, valeric, isovaleric, trimethylacetic, Z-methylbutyric,3-ethylbutyric, h'exanoic, diethylacetic, triethylacetic, heptanoic,octanoic, ewethylisovaleric,

or other hydrocarbon carboxylic acid esters thereof are containing fromone to twelve carbon atoms, inclusive, e. cyclopropylideneacetic,cyclopentylformic, cyclopentylacetic, fl-cyclopentylpropionic,cyclohexylformic, cyclohexylacetic, fi-cyclohexylpropionic, an aryl oralkaryl acid, e. g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4-,2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic,2,4,6-trimethylbenzoic, a-naphthoic, 3-methyl-mnaphthoic, phenylacetic,phenylpropionic, etc.

17-carboxylic acid esters of 9(ll)-dehydro-17-ethyltestosterone areprepared in the same manner from 9( l l dehydro-l7-ethyltestosterone.

Example 5,-: bromo 11p hydroxy 17 methyl testosterone (V) To a solutionof one gram of 9(11)-dehydro-l7-methyltestosterone (IV) in fiftymilliliters of acetone was added dropwise, with stirring, at fifteendegrees centigrade, one gram of N-bromoacetamide dissolved in 25milliliters of water. A solution of twenty milliliters of 0.8 N perchloric acid was then slowly added at the same temperature. After twentyminutes, there was added a sufficient amount of a saturated aqueoussolution of sodium sulfite to discharge the yellow color of thesolution. The resulting mixture was then diluted with milliliters ofwater thereby precipitating one gram of9n-bromo-l1phydroxy-l7-methyltestosterone as needles melting at 153 to155 degrees centigrade.

Similarly, l7-carboxylic acid esters of 9(l1)-dehydro-17-methyltestosterone (V, R=CHa, R'=-Ac), e. g., an ester named in theparagraph following Example 4, preferably the acetate, are similarlyconverted to a 17- carboxylic acid ester of 9a-bromo-l lfl-hydroxy-17-methyltestosterone.

Reacting 9c: bromo 11,3 hydroxy l7 methyl testosterone or a l7-esterthereof named above, with sodium iodide in acetone, according totechniques known in the art, is productive of 9a-iodo-l1fl-hydroxy47-methyltestosterone and esters thereof, respectively.

90:. bromo 11B hydroxy l7 ethyltestosterone and 17-carboxylic acidesters thereof are similarly prepared by substituting9(l1)-dehydro-l7-ethyltestosterone and 17-carboxylic acid estersthereof, respectively, as the starting steroid in the reaction describedin Example 5.

In the reaction of Example 5, the N-bromoacetamide produces hypobromousacid in situ. Other N-bromoamides and N-bromoimides may be used or asolution of hypobromous acid per se may be used.

Example 6 .9,1 1,8-epoxy-1 7-methyltestoster0ne (VI) A suspension of onegram of 9a-bromo-llfi-hydroxyl7-methyltestosterone (V) in thirtymilliliters of methanol was titrated with one molar equivalent of 0.1 Naqueous sodium hydroxide. The resulting mixture was diluted with fiftymilliliters of water and then chilled to about zero degrees centigradethereby precipitating 0.64 gram of 9,1lfi-epoxy-l7-methyltestosteronemelting at to 176 degrees centigrade which, after crystallization fromdilute methanol, melted at 65 to 172 degrees centigrade withsublimation) and had an [661D of minus forty degrees in chloroform andthe analysis below.

Calculated for CaoHzsOa: C, 75.92; H, 8.92. Found: C, 75.60; H, 8.96.

In the same manner as described in Example 6, 17- esters of9a-bromo-llp-hydroxy-l7-methyltestosterone, e. g.,9a-bromo-11,B-hydroxy-l7-methyltestosterone, l7- acylates wherein theacyl radical is that of an acid named in the paragraph following Example4, are converted to l7-carboxylic acid esters of9,1lfl-epoxy-l7-methyltestosterone.

9,1 lfi-epoxy-17-methyltestosterone and l7-carboxylic acid estersthereof are also prepared by substituting 9aiodo-l lfi-hydroxy- 17methyltestosterone and 17-carboxylic acid esters thereof, respectively,as the starting steriod in the reaction described in Example 6.

9,1lp-epoxy-l7-ethyltestosterone and 17-carboxylic acid similarlyprepared by substituting 9abromolLB-hydcoxy l7-ethyltestosterone and17-carboxylic acid esters thereof, respectively, as the starting steroldin the reaction described in Example 6.

Example 7.9m-fluoro-I I B-hydrxy-I 7- methyltestosterone V11) To asolution of 0.5 gram of 9,11,6-epoxy-l7-methyltestosterone (VI) in tenmilliliters of methylene chloride was added two milliliters of 48percent aqueous hydrofluoric acid. The mixture was stirred. at roomtempera ture for five hours and then cautiously poured with stirringinto a mixture of six grams of sodium bicarbonate in a mixture of iceand water. The precipitated steroid was extracted with methylenechloride, the extract washed with water and then dried. The solvent wasdistilled from the dried solution and the residue crystallized frommethylene chloride to give 148 milligrams of9a-fluorollB-hydroxy-l7-methyltestosterone melting at 265 degreescentigrade with decomposition, having an [111D of plus 110 degrees inchloroform and the analysis below.

Calculated for CzoHzsOsF: C, 71.40; H, 8.69; F, 5.65. Found: C, 71.71;H, 8.66; F, 5.75.

Similarly, 90z-flHOIO-l lfl-hydroxy-l7-ethyltestosterone is prepared bysubstituting 9,1l,3-epoxy-7-ethyltestosterone as the starting steroid inExample 7.

Example 8.-9a-flu0ro-1 I B-hydroxy-I 7-methyltestosterone, 1 7-acetate(VII) Following the procedure of Example 7 exactly, but substituting amolar equivalent of 9,1lp-epoxy-17-methyltestosterone, l7-acetate as thestarting steroid, there is thus-produced 9u-fluoro-I l p-hydroxy-l7-methyltestosterone, l7-acetate.

Following the procedure described in Example 8, but substituting asstarting steroid another l7-carboxylic acid ester of9,1lfl-epoxy-l7-methyltestosterone, e. g., a 9,116-epoxy-l7-methyltestosterone, l7-acylate wherein the acyl radical is thatof an acid named in the paragraph following Example 4, there isthus-produced other l7-esters of9a-fluoro-llfi-hydroxy-l7-methyltestosterone, e. g., 9ailuoro 115hydroxy l7 methyltestosterone, l7 acylates wherein the acyl radical isthat of a hydrocarbon carboxylic acid containing from one to twelvecarbon atoms, for example, a lower-aliphatic acid, e. g., formic,propionic, butyric, isobutyric, Valerie, isovalcric, trimethylacetic,Z-methylbutyric, 3-ethylbutyric, hexanoic, diethylacctic,triethylacetic, heptanoic, octanoic, til-ethylisovaleric,cyclopropylideneacetic, a cycloaliphatic acid, e. g., cyclopcntylformic,cyclopentylacetic, fl-cyclopentylpropionic, cyclohexylformic,cyclohexylacetic, ficyclohexylpropionic, an aryl or al karyl acid, e.g., benzoic, 2', 11-, or 4-methylbcnzoic, 2,3-, 2,4-, 2,5-, 2.6-, 3.4-and 3,5- dirnethylbenzoic, ethylbenzoic, 2,4,6-trimethylbenzoic,anaphthoic, 3-methyl-u-naphthoic, an aralkyl acid, e. g., phenylacetic,phenylpropionic, etc.

Similarly, 9m-finoro-l lB-hydroxy-17-ethyltestosterone, 17-acylates areprepared by substituting a 9,11B-epoxy- 7-ethyltestosterone, 17-acylate,e. g., wherein the acyl radical is that of an acid named in theparagraph following Example 8, as the starting steroid in the reactionof Example 8.

Example 9.-9a-chl0r0-I I 13-h ydrox y-I 7- methyltestosterone the acylradical is that of an acid named in the paragraph following Example 4.are produced by substituting :1 9,1lthepoxyd7-methyltestosterone,l7-acylate, e. g., wherein the acyl radical is that of an acid named inthe paragraph following Example 4, as the starting steroid in thereaction described in Example 9.

Following theprocednrecf Example 9, but substituting as starting storied9,llp-epoury-l7-ethyltestosterone or a 9,11fi-epoxyl7-ethyltestosterone,l7-acylate wherein the acyl radical is, for example, that of an acidnamed in the paragraph following Example 4, there is thus produced 9e:chloro 11,9 hydroxy l7 ethyltestosterone and9a-chloro-l7-ethyltestosterone, l7'acylates, respectively.

The 9u-Chl010- and 9a-fluoro-llfi hydroxy-fl-alkyltcstostcrones,l7-acylates named above are also prepared by esterification of thecorresponding free 17-hy'droxy compounds in the manner described inExample 4.

Example 10.-9wfluoro-I I-keto-I 7-methylrest0sterone VIII) To a solutionof 0.457 gram of QaL-fltlOl'O-l lfl hydroxyl7-methyltestosterone (VII)in twenty milliliters of glacial acetic acid was added a solution of0.25 gram of chromium trioxide and one milliliter of water in twentymilliliters of acetic acid. The mixture was maintained at roomtemperature for 4.5 hours and then mixed with five milliliters ofmethanol. The solvent was removed by distillation at reduced pressureand the almost dry residue mixed with twenty milliliters of water. Theprecipitate was filtered, washed with water and then dried to give 0.362gram of 9m-fluoro-ll-keto-l7-methyltestosterone melting at 208 to 212degrees Centigrade and, after crystallization from dilute methanol andthen from a mixture of acetone and hexane hydrocarbons, melting at 213to 220 degrees centigrade, having an [021D of plus 144 degrees inchloroform and the analysis below.

Calculated for CzoI-IaiOaF: C, 71.83; H, 8.14; F, 5.68. Found: C, 72.13;H, 8.30; F, 5.83.

Following the procedure described in Example 10, but substituting asstarting steroid a 9a-fiuoro-11B-hydroxy-17 methyltestosterone,17-acylate named in the paragraph following Example 4, there is thusproduced esters of 9w fluoro-ll-keto-17-methyltestosterone, e. g.,9a-fiuoro-11- keto-l7-methyltestosterone, l7-aeylates wherein the acylradical is, for example, that of an acid named in the paragraphfollowing Example 4.

Similarly, substituting Qu-chloro-l 1 fl-hydroxy-l7-methyltcstosteroneas the starting steroid in the reaction described in Example 10, thereis thus-produced t-Chi01'0- l 1 -keto-17-methyltestosterone.

Substituting 9m-fluoro-1 l B-hydroxyl 7-ethyltestosterone or9a-fiuoro-1lfi-hydroxy-l7-ethyltestosterone, 17-acylates wherein theacyl radical is, for example, that of an acid named in the paragraphfollowing Example 8 as the starting steroid in Example 10, there isthus-produced 9ailuoro-l l-keto-17-ethyltestosterone and9ui-fluoro-11-ketol7-ethyl-testosterone, l7-acylates, respectively. The911- chloro-ll-keto-l7-ethyltestostcrone and 17-acylates thereof aresimilarly prepared from the corresponding 9mchloro-l lp-hydroxycompounds.

3-ker0-9a-flimro-1 7a-metIzyl-1,4-androstadiene-I I 3,] 7,3- diol Eightmilliliters (0.068 mole) of ethyl oxalate and 10.6 milliliters (0.023mole) of a 2.2 Normal methanolic solution of sodium mcthoxide is addedto a solution of 6.3 grams (0.021 mole) of9(1l)-dehydro-17-rnethyltestosterone in milliliters of anhydroustertiary butyl alcohol at about fifty degrees centigrade. The mixture ismaintained at room temperature for three hours, during which time thesodium enolate of 2-ethoxyoxalyl-9( l l )-dehydrol7-methyltestosteroneprecipitates. The mixture is neutralized With glacial acetic acid.

To the thus-obtained solution of the 2-ethoxyoxalyl-9(1l)dehydro-l7-mc'thyltcstosterone is added milliliters of methanol,the mixture cooled to zero degrees centigrade in an ice bath and asolution of 3.7 grams (0.023 mole) of bromine in 74 milliliters ofmethanol is then added dropwise thereto over a period of about fifteenminutes to produce2-brorno-2-ethoxyoxalyl-9U1)-dehydro-l7-methyltestosterone. To theresulting mixture is then added about 25 milligrams of phenol and 33milliliters (0.05 mole) of a 1.5 Normal methanolic solution of sodiummethoxide whereafter the mixture is heated for five minutes on a steambath followed by the addition of the cooled solution to water. Aprecipitate of 2-bromo-9(11)- dehydro-l7-methyltestosterone forms, whichis thoroughly washed with water and dried in a vacuum desiccator.

A mixture of 758 milligrams (0.2 millimole) of 2-bromo-9(ll)'dehydro-l7-methyltestosterone and 1.2 milliliters of-collidine is heated at the refluxing temperature of the mixture forthirty minutes and then cooled to room temperature. The cooled mixtureis diluted with ether and the collidine hydrobromide which precipitatesis filtered from the solution. The filtrate is washed with dilutesulfuric acid followed by water and then dried over anhydrous sodiumsulfate. The dried solution is freed of solvent and the oily residuechromatographed over four grams of alumina. The column is developed withSkellysolve B hexane hydrocarbons containing increasing amounts ofacetone. 3-keto-17u-methyl-1,4,9(11)- androstatrien-UB-ol is thusisolated from the other reaction products.

Following the procedures of Examples 5 to 7 exactly, but substituting3-keto-l7ot-methyl-1,4,9( l l )-androstatrien-l7B-ol as the startingsteroid, there is thus-produced l-dehydro-9a-fluoro1lfi-hydroxy-l7-methyltestosterone which is converted to l7-hydrocarboncarboxylic acid esters thereof according to the procedure of Example 8and the paragraph following.l-dehydro-9u-chlorollfihydroxy-l7-methyltestosterone is similarlyprepared according to the procedure of Example 9, employing 3-ketol7a-methyl-9,1 lfi-epoxy-l ,4-androstadien- 175-01 in the reactiondescribed in Example 9. Its l7-acetate is prepared by substitution ofthe free alcohol as the starting steroid of Example 8. Otherl7-hydrocarbon carboxylic acid esters are prepared in the mannerdescribed in the paragraph following Example 8.ldehydro-9a-fluoroll-keto-17-methyltestosterone and its esters areprepared by substituting l-dehydro9a-fluoro-llfl-hydroxy-l7-methyltestosterone and its l7esters, respectively, in thereaction described in Example 10.

The application is a division of application Serial No. 527,118, filedAugust 8, 1955.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications will be apparent to one skilled in the art, andthe invention is therefore to be limited only by the scope of theappended claims.

I claim:

1. 9a-halo-ll-keto-l7-alkyltestosterones the following formularepresented by OHIQ wherein X is a halogen having an atomic weight from19 to 36, inclusive.

3. 9e-fluoro-1l-keto-17-methyltestosterone.

No references cited.

1. 9A-HALO-11-KETO-17-ALKYLTESTOSTERONES REPRESENTED BY THE FOLLOWINGFORMULA